Discovery of new sulfonamide-tethered 2-aryl-4-anilinoquinazolines as the first-in-class dual carbonic anhydrase and EGFR inhibitors

Abstract

In today's medical field, there is a growing trend of exploiting a single small molecule to target two different molecular targets concurrently. This approach is proving to be highly effective in fighting against cancer. The 4-anilinoquinazoline scaffold, known for its potential in cancer therapy and its effectiveness as a leading class of tyrosine kinase inhibitors, was employed to develop a novel series of anilinoquinazoline-sulfonamides (AQSs) (8a-d, 9a-f, and 10a-d) as dual inhibitors of the tumor-associated carbonic anhydrases (CA) IX/XII and EGFR. 2-(3-Methoxyphenyl)quinazoline bearing p-sulfanilamide 10b elicited superior hCA IX and XII inhibition in the low nanomolar range (K_Is = 38.4 and 8.9 nM, respectively). Also, 10b shined as a potent and selective EGFR inhibitor, boasting an impressive IC₅₀ value of 51.2 ± 0.97 nM, surpassing the reference EGFR inhibitor Erlotinib (IC₅₀ = 80 ± 2.0 nM). Compound 10b exhibited broadest-spectrum antiproliferative activity against the NCI-tumor panel with a mean GI% value of 68 %. Of special interest, 10b demonstrated potent growth inhibition (GI% ≥ 80-97 %) toward cell lines reported to express high levels of EGFR belonging to renal, colon, breast, and lung cancers. Compound 10b's molecular docking in the CA IX/XII and EGFR active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated strong and stable interactions of 10b with the binding sites of these targets.

Keywords: 4-Aminoquinazolines; Hypoxic tumors; Kinase inhibitor; Molecular dynamics; Synthesis.